Alcoholic Liver Disease (ALD) is caused by excessive long term consumption of alcohol via increased oxidative stress, reduction of oxygen to liver tissue (hypoxia), altered fat metabolism, increased pro-inflammatory signaling molecules (or cytokines), and increased inflammation. ALD begins with increased fat deposit in the liver. With continued excessive alcohol consumption, disease severity increases as the inflammatory component accelerates, leading to the disease states referred to as alcoholic steatohepatitis (ASH) or alcoholic hepatitis (AH). Persistent alcohol consumption then leads to extensive liver cell death and fibrosis (scarring). Extensive fibrosis results in cirrhosis and ultimately liver failure necessitating liver transplantation. It is estimated that more than 2 million people in the U.S. have ALD and in 2006, chronic liver disease with cirrhosis was the 12th leading cause of death in the U.S. with ~46% of deaths directly related to alcohol (National Vital Statistics Reports, 2007). The overall cost of health care expenditures associated with alcohol consumption was estimated at $26 billion in 1998 in the U.S. (NIAAA website). Cardax Pharmaceuticals, Inc. (Cardax) is developing a novel, proprietary, orally bioavailable small molecule, Heptax, which exhibits robust anti-inflammatory, anti-oxidant activity in relevant animal models of ALD. The compound accumulates in cellular membranes including those of liver mitochondria where much of the pro-inflammatory oxidative stress occurs. Animal studies with oral Heptax as well as human exposure through diet or dietary supplements of the active metabolite have demonstrated an unusually benign safety profile. The goal of this Fast Track Phase I/II SBIR grant is to advance the preclinical development and understanding of Heptax for the treatment of Alcoholic Liver Disease (ALD). Specifically, the grant proposes: 1) 7 day and 4 week toxicity studies of Heptax;2) expanding the understanding of Heptax in various animal models of liver disease;and 3) pilot plant production (including process development) of the kilogram quantities of Heptax necessary for these studies. The 4 week toxicity study reports would be suitable for inclusion as part of an Investigational New Drug (IND) application to the FDA to begin human clinical trials. Company personnel are highly qualified to supervise and coordinate this activity. Cardax also has significant in-house bioanalytical capability and will transfer its proprietary bioanalytical methods to the independent contract laboratories that will perform the bioanalysis required by the FDA. Cardax will provide oversight and validation. The additional animal efficacy work will be undertaken in collaboration with experienced investigators with Cardax personnel supplying oversight, co-design, and review capabilities. PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease affects more than 2,000,000 people in the U.S., resulting in significant illness and death with minority groups disproportionately affected. Current treatments are expensive, can have significant side effects, and are only marginally effective. A safer, more efficacious, and economical therapy for this disease would represent a major medical breakthrough for this under-served population.